Diabetes is a disease with a persistent hyperglycemia, and it is considered that many environmental factors and genetic factors cause diabetes. A main factor regulating blood glucose is insulin, and it is known that a deficiency of insulin or a redundant presence of various factors inhibiting the activities of insulin (such as genetic factors, lack of exercise, fatness, stress, or the like) cause hyperglycemia.
There are two major types of diabetes, which are classified into an insulin dependent diabetes mellitus (IDDM) caused by a decreased pancreatic insulin secretion due to an autoimmune disease or the like, and a noninsulin dependent diabetes mellitus (NIDDM) caused by a decreased pancreatic insulin secretion due to an exhausted pancreas with a continuous hypersecretion of insulin. It is considered that 95% or more of Japanese patients with diabetes are NIDDM, and there is a problem in that the number of patients increases in accordance with changes of life-style.
As the treatment of diabetes, a diet therapy, a kinesitherapy, a remedy for fatness, or the like are mainly carried out in mild cases, an oral medicament for diabetes (for example, an agent for promoting insulin secretion such as sulfonylureas) is administered when symptoms become severe, and an insulin preparation is administered in serious cases [Ryuzo Abe and Masato Kasuga, “An Approach to EBM on the Treatment of Diabetes Mellitus”, Nankodo, 1997; Richard A. Harrigan et al., Annals of Emergency Medicine, 38(l), 68-78, 2001; and Japan Diabetes Society, “Tounyoubyou chiryou gaido 2000 (Treatment of diabetes mellitus, Guide 2000)”, Bunkodo, 2000].
Sulfonylureas stimulate pancreatic β cells and promote insulin secretion. However, the timing of insulin secretion and an amount of insulin secreted are decided by the timing of a medicament administration and its dose, regardless of a blood glucose level. Therefore, hypoglycemia caused by a maintenance of the medicament activity, as a side effect, sometimes occurs. Further, symptoms in the digestive system such as loss of appetite occur. Furthermore, sulfonylureas are contraindicated for patients with a hepatic or renal dysfunction or severe ketosis [Richard A. Harrigan et al., Annals of Emergency Medicine, 38(1), 68-78, 2001].
The insulin preparations certainly decrease blood glucose. However, they must be administered by injection, and they sometimes cause hypoglycemia [McCrimmon R J et al., Diabete. Metab., 20(6), 503-512, 1994].
As described above, conventionally used agents for promoting insulin secretion and insulin preparations have these problems. Therefore, agents capable of a advanced control of blood glucose, i.e., agents not simply decreasing blood glucose but capable of controlling blood glucose within a normal range, are desired.
It is known that GLP-1 (Glucagon-like peptide-1), PACAP (Pituitary adenylate cyclase activating polypeptide), and GIP (Gastric inhibitory polypeptide) transduce a signal into a cell via their own specific G protein-coupled receptors, and promote insulin secretion. These G protein-coupled receptors are receptors which are coupled to a Gs protein, activate adenylate cyclase, and increase an intracellular cAMP concentration. Further, it is known that a GLP-1 receptor, a PACAP receptor, and a GIP receptor promote insulin secretion by increasing the intracellular cAMP concentration. However, it is known that the expression of these G protein-coupled receptors is distributed in pancreas but is not pancreas-specific [Dunphy J L et al., Mol. Cell. Endocrinol., 141(1-2), 179-186, 1998; Timothy James Kieffer et al., Endocrine Reviews, 20(6), 876-913, 1999; David Vaudry et al., Pharmacological Reviews, 52(2), 269-324, 2000; Jean Claude Reubi et al., Cancer Research, 60, 3105-3112, 2000; and Ted B. Usdin et al., Endocrinology, 133(6), 2861-2870, 1993], and that the activation of the GIP receptor is not effective in NIDDM (Michael A. Nauck et al., J. Clin. Invest., 91, 301-307, 1993).
In this connection, nucleotide sequences encoding the same amino acid as that of a “polypeptide having an amino acid sequence of SEQ ID NO: 2” which may be used in the present invention, and deduced amino acid sequences encoded by the nucleotide sequences are reported (WO00/22131, WO00/31258, and WO00/50562 pamphlets). However, functions of the “polypeptide having an amino acid sequence of SEQ ID NO: 2” in a body were not clearly described in these reports. For example, the polypeptide is described as a human orphan G protein-coupled receptor in the WO00/22131 and WO00/31258 pamphlets. The WO00/50562 pamphlet lists, as a use of both agonists and antagonists of the “polypeptide having an amino acid sequence of SEQ ID NO: 2”, many of the same diseases with respect to both the agonists and antagonists, but does not disclose any support that the agonists or antagonists are useful for treating these diseases.